CN108379251A - Glycosyl polyethers class compound is found as the new mechanism research of anticancer drug - Google Patents
Glycosyl polyethers class compound is found as the new mechanism research of anticancer drug Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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Abstract
The invention discloses polyether compounds in anti-tumor aspect study on mechanism.The drug is for acting at least one following signal path：By influencing apoptosis, the apoptosis by influencing the horizontal apoptosis mediated of reactive oxygen species (ROS), the cromoci level mediation for influencing cell mitochondrial that calcium ion induces.The polyether compound of the present invention can play preferable anticancer effect by regulating and controlling many A signal pathways so as to cause the death of tumour cell.
Description
Technical field
The present invention relates to biomedicine fields.In particular it relates to which polyether compound is as the new of anticancer drug
Mechanism Study is found.
Background technology
Polyether antibiotics are a kind of I important type polyketides generated by streptomycete, at present mainly as pre-
Anti- zoogenetic infection globidiosis and the veterinary drug for improving efficiency of feed utilization promotion growth, such as：Salinomycin, lasalocid, Buddhist nun day
Leah mycin and Maduamicin A etc..It has had more than 120 kinds of polyether compounds till now to be found to report, polyethers
Closing object carrier has chelated mineral cation (Na+、K+、Ca2+) ability, form fat-soluble compound, carrier can be from cell
It extends out and is dissipated into the cell, and return to extracellularly or stay on cell membrane and commuted into the cell as metal ion transport agent
Outside, promote the transmembrane process of metal ion.
However, the mechanism of action of the antitumor activity of polyether antibiotics performance at present still requires study.
Invention content
The present invention is directed to solve one of the technical problems existing in the prior art at least to a certain extent.For this purpose, this hair
It is bright to propose a kind of polyether compound and found as the new mechanism research of anticancer drug.
It should be noted that the present invention is the following discovery based on inventor and completes：
Inventor find, polyether compound have specificity inhibit tumour cell and tumor stem cell proliferation, differentiation
Ability.In turn, inventor is had found by furtheing investigate, and polyether compound can be by regulating and controlling many A signal pathways, to draw
The death for playing tumour cell, plays preferable anticancer effect.
For this purpose, in one aspect of the invention, the present invention proposes a kind of polyether compound as the new of anticancer drug
Mechanism Study is found.The drug is for regulating and controlling at least one following signal path：By influence calcium ion induction apoptosis,
What the cromoci level by influencing the horizontal apoptosis mediated of reactive oxygen species (ROS), influence cell mitochondrial mediated withers
It dies, the polyether compound has one of following structure：
And
Inventor passes through many experiments, and polyether compound is capable of the expression and protein phosphorylation water of modulin
It is flat, to regulate and control above-mentioned many A signal pathways, to inhibit proliferation, the differentiation of tumour cell or tumor stem cell, its apoptosis is inspired,
Play preferable anticancer effect.
According to an embodiment of the invention, the purposes of above-mentioned polyether compound in medicine preparation can also have following attached
Add technical characteristic：
According to an embodiment of the invention, the drug regulates and controls the apoptotic signal by least one following form and leads to
Road：By influencing the apoptosis of calcium ion induction, by influencing the horizontal apoptosis mediated of reactive oxygen species (ROS), influencing cell
The apoptosis that the cromoci level of mitochondria mediates inspires to inhibit proliferation, the differentiation of tumour cell or tumor stem cell
Its apoptosis plays preferable anticancer effect.
According to an embodiment of the invention, the drug regulates and controls the calcium signal by least one following form and leads to
Road：Promote albumen (the Plasma membrane calcium-transporting ATPase) expression of ATP2B1 gene codes；
Promote albumen (Calcium-binding mitochondrial carrier protein) table of SLC25A24 gene codes
It reaches；Promote albumen (the Calcium-binding mitochondrial carrier protein of SLC25A13 gene codes
Aralar2 it) expresses；Promote albumen (the Calcium-binding mitochondrial carrier of SLC25A12 gene codes
Protein Aralar1) expression；Promote the albumen (Sarcoplasmic/endoplasmic of ATP2A2 gene codes
Reticulum calcium ATPase) expression；Promote albumen (the Calpain small subunit of CAPNS1 gene codes
1) it expresses；Promote albumen (Calpain-2catalytic subunit) expression of CAPN2 gene codes；Promote in tumour cell
Calcium ion concentration increases；Its apoptosis is inspired, preferable anticancer effect is played.
According to an embodiment of the invention, the drug is horizontal by influencing active oxygen ROS in tumour cell, described in regulation and control
The Apoptosis that ROS is mediated.Inventor has found that polyether compound is horizontal by raising ROS, activates ROS mediated apoptosis signals,
To inhibit proliferation, the differentiation of tumour cell or tumor stem cell, its apoptosis is inspired, preferable anticancer effect is played.
According to an embodiment of the invention, it is logical to regulate and control the apoptotic signal by influencing expression of cytochrome C for the drug
Road.Inventor has found that polyether compound promotes the cromoci of UQCRC1 gene codes by raising cromoci level
(Cytochrome b-c1 complex subunit 1) is expressed；Promote the cromoci of UQCRC2 gene codes
(Cytochrome b-c1 complex subunit 2) is expressed；Promote the cromoci of CYC1 gene codes
(Cytochrome c1) is expressed；Promote cromoci (the Cytochrome b-c1 complex of UQCRB gene codes
Subunit 7) expression；Promote the cromoci (Cytochrome c) of CYCS gene codes；Active cell apoptosis, to press down
The proliferation of tumour cell or tumor stem cell processed, differentiation, inspire its apoptosis, play preferable anticancer effect.
In another aspect of this invention, the present invention proposes a kind of method of screening anticancer drug.Reality according to the present invention
Example is applied, the method includes：
(1) Candidate Agents are contacted with cancer cell, and detect whether the front and back signal path of contact is adjusted,
The signal path includes at least one of following：By influencing the apoptosis of calcium ion induction, by influencing cell
The horizontal apoptosis mediated of interior active oxygen (ROS) influences the apoptosis that the cromoci level of cell mitochondrial mediates；
(2) after the contact, the signal path is adjusted the finger for being the Candidate Agents as the anticancer drug
Show.
Inventor has found that above-mentioned signal path and the proliferation of cancer cell, differentiation are closely identical, if the above-mentioned signal of cancer cell
Access is adjusted, and can be inhibited its proliferation, differentiation, be inspired its apoptosis.It in turn, can if after Candidate Agents contact with cancer cell
So that above-mentioned signal path is adjusted, so as to determine that the medicament has effects that anticancer.
According to an embodiment of the invention, in step (1), at least one following albumen or ion concentration before and after detection contact
Expression quantity：The albumen (Plasma membrane calcium-transporting ATPase) of ATP2B1 gene codes,
Albumen (Calcium-binding mitochondrial carrier protein) c-Myc eggs of SLC25A24 gene codes
In vain, albumen (the Calcium-binding mitochondrial carrier protein of SLC25A13 gene codes
Aralar2), albumen (the Calcium-binding mitochondrial carrier protein of SLC25A12 gene codes
Aralar1), albumen (the Sarcoplasmic/endoplasmic reticulum calcium of ATP2A2 gene codes
ATPase), Ca in tumour cell2+Active oxygen ROS is horizontal in concentration, tumour cell, cromoci of UQCRC1 gene codes
Cromoci (the Cytochrome b-c1 of (Cytochrome b-c1complex subunit 1), UQCRC2 gene codes
Complex subunit 2), the cell of the cromoci (Cytochrome c1) of CYC1 gene codes, UQCRB gene codes
Cromoci (the Cytochrome of pigment C (Cytochrome b-c1 complex subunit 7), CYCS gene codes
c)；In step (2), after contact, albumen (the Plasma membrane calcium- of the ATP2B1 gene codes
Transporting ATPase), albumen (the Calcium-binding mitochondrial of SLC25A24 gene codes
Carrier protein) c-Myc albumen, SLC25A13 gene codes albumen (Calcium-binding
Mitochondrial carrier protein Aralar2), the albumen (Calcium-binding of SLC25A12 gene codes
Mitochondrial carrier protein Aralar1), the albumen (Sarcoplasmic/ of ATP2A2 gene codes
Endoplasmic reticulum calcium ATPase), albumen (the Calpain small of CAPNS1 gene codes
Subunit 1), the albumen (Calpain-2catalytic subunit) of CAPN2 gene codes, Ca in tumour cell2+Concentration,
Active oxygen ROS is horizontal in tumour cell, cromoci (Cytochrome b-c1 complex of UQCRC1 gene codes
Subunit 1), cromoci (Cytochrome b-c1complex subunit 2), the CYC1 bases of UQCRC2 gene codes
Because of the cromoci (Cytochrome c1) of coding, cromoci (the Cytochrome b-c1 of UQCRB gene codes
Complex subunit 7), the cromocis (Cytochrome c) of CYCS gene codes；At least one expression quantity improve
It is instruction of the Candidate Agents as the anticancer drug.
Inventor's discovery, albumen (the Plasma membrane calcium-transporting of ATP2B1 gene codes
ATPase), the albumen (Calcium-binding mitochondrial carrier protein) of SLC25A24 gene codes
Albumen (the Calcium-binding mitochondrial carrier of c-Myc albumen, SLC25A13 gene codes
Protein Aralar2), albumen (the Calcium-binding mitochondrial carrier of SLC25A12 gene codes
Protein Aralar1), albumen (the Sarcoplasmic/endoplasmic reticulum of ATP2A2 gene codes
Calcium ATPase), the albumen (Calpain small subunit 1) of CAPNS1 gene codes, CAPN2 gene codes
Ca in albumen (Calpain-2catalytic subunit), tumour cell2+In concentration, tumour cell active oxygen ROS it is horizontal,
The cromocis (Cytochrome b-c1 complex subunit 1) of UQCRC1 gene codes, UQCRC2 gene codes
The cromoci of cromoci (Cytochrome b-c1complex subunit 2), CYC1 gene codes
The cromoci (Cytochrome b-c1 complex subunit 7) of (Cytochrome c1), UQCRB gene codes,
The expression quantity of cromoci (Cytochromec) at least one of which of CYCS gene codes improves, and it is thin can to significantly inhibit cancer
The proliferation of born of the same parents, differentiation, inspire its apoptosis.In turn, if Candidate Agents have above-mentioned function and effect, it is anti-to can determine that the medicament has
The effect of cancer.
According to an embodiment of the invention, in step (1), the albumen of the front and back ATP2B1 gene codes of detection contact
Albumen (the Calcium- of (Plasma membrane calcium-transporting ATPase), SLC25A24 gene codes
Binding mitochondrial carrier protein) c-Myc albumen, SLC25A13 gene codes albumen
The egg of (Calcium-binding mitochondrial carrier protein Aralar2), SLC25A12 gene codes
The egg of (Calcium-binding mitochondrial carrier protein Aralar1), ATP2A2 gene codes in vain
The albumen of (Sarcoplasmic/endoplasmic reticulum calcium ATPase), CAPNS1 gene codes in vain
The albumen (Calpain-2catalytic subunit) of (Calpain small subunit 1), CAPN2 gene codes swells
Ca2+ concentration in oncocyte, active oxygen ROS is horizontal in tumour cell, cromoci (Cytochrome of UQCRC1 gene codes
B-c1 complex subunit 1), cromoci (the Cytochrome b-c1 complex of UQCRC2 gene codes
Subunit 2), the cromoci of the cromoci (Cytochrome c1) of CYC1 gene codes, UQCRB gene codes
The cromoci (Cytochrome c) of (Cytochrome b-c1 complex subunit 7), CYCS gene codes is at least
One of quantity；
In step (2), after contact, albumen (the Plasma membrane of the ATP2B1 gene codes
Calcium-transporting ATPase), the albumen (Calcium-binding of SLC25A24 gene codes
Mitochondrial carrier protein) c-Myc albumen, SLC25A13 gene codes albumen (Calcium-
Binding mitochondrial carrier protein Aralar2), the albumen of SLC25A12 gene codes
The albumen of (Calcium-binding mitochondrial carrier protein Aralar1), ATP2A2 gene codes
The albumen of (Sarcoplasmic/endoplasmic reticulum calcium ATPase), CAPNS1 gene codes
The albumen (Calpain-2catalytic subunit) of (Calpain small subunit 1), CAPN2 gene codes swells
Ca in oncocyte2+Active oxygen ROS is horizontal in concentration, tumour cell, cromoci (Cytochrome of UQCRC1 gene codes
B-c1 complex subunit 1), cromoci (the Cytochrome b-c1 complex of UQCRC2 gene codes
Subunit 2), the cromoci of the cromoci (Cytochrome c1) of CYC1 gene codes, UQCRB gene codes
The increasing of the cromoci (Cytochrome c) of (Cytochrome b-c1 complex subunit 7), CYCS gene codes
Mostly it is instruction of the Candidate Agents as the anticancer drug.
Inventor's discovery, albumen (the Plasma membrane calcium-transporting of ATP2B1 gene codes
ATPase), the albumen (Calcium-binding mitochondrial carrier protein) of SLC25A24 gene codes
Albumen (the Calcium-binding mitochondrial carrier of c-Myc albumen, SLC25A13 gene codes
Protein Aralar2), albumen (the Calcium-binding mitochondrial carrier of SLC25A12 gene codes
Protein Aralar1), albumen (the Sarcoplasmic/endoplasmic reticulum of ATP2A2 gene codes
Calcium ATPase), the albumen (Calpain small subunit 1) of CAPNS1 gene codes, CAPN2 gene codes
Ca in albumen (Calpain-2catalytic subunit), tumour cell2+In concentration, tumour cell active oxygen ROS it is horizontal,
The cromocis (Cytochrome b-c1 complex subunit 1) of UQCRC1 gene codes, UQCRC2 gene codes
The cromoci of cromoci (Cytochrome b-c1complex subunit 2), CYC1 gene codes
The cromoci (Cytochrome b-c1 complex subunit 7) of (Cytochrome c1), UQCRB gene codes,
The cromoci (Cytochrome c) of CYCS gene codes increases, and can significantly inhibit proliferation, the differentiation of cancer cell, promote
Send out its apoptosis.In turn, if Candidate Agents have above-mentioned function and effect, it can determine that the medicament has effects that anticancer.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
Obviously, or practice through the invention is recognized.
Description of the drawings
The above-mentioned and/or additional aspect and advantage of the present invention will become in the description from combination following accompanying drawings to embodiment
Obviously and it is readily appreciated that, wherein：
Fig. 1 shows the chromatogram of J1001-2 compounds according to an embodiment of the invention；
Fig. 2 shows the chromatogram of J1001-3 compounds according to an embodiment of the invention；
Fig. 3 shows the chromatogram of J1001-4 compounds according to an embodiment of the invention；
Fig. 4 shows the chromatogram of J1-001 compounds according to an embodiment of the invention；
Fig. 5 shows according to an embodiment of the invention by protein groups discovery J1001-2 induced cytochromes C increasings
Add；
Fig. 6 shows that according to an embodiment of the invention induced by protein groups discovery J1001-2 participates in calcium ion
GAP-associated protein GAP situation of change.
Fig. 7 shows that J1001-1 and J1001-2 according to an embodiment of the invention cause ROS in tumour cell horizontal
Variation；
Fig. 8 and Fig. 9 shows that J1001-1 and J1001-2 according to an embodiment of the invention cause calcium in tumour cell
Ion concentration changes.
Specific implementation mode
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it is carried out according to technology or condition described in document in the art or according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
The preparation method of 1 polyether compound of embodiment
By one plant of Streptomyces nanchangensis hypotype, two plants of Streptomyces hygroscopicus are sub-
Type and one plant of Streptomyces endus hypotypes streptomycete are inoculated in SFM tablets respectively, cultivate three days to four days or so.It waits for
When forming bacterium colony in SFM culture mediums, chooses single bacterium and drop down onto in seed culture medium and cultivate three days to four days or so, connect according to 1% amount
To fermentation medium, (composition of fermentation medium is soluble starch 30g/L, soybean cake powder 10g/L, yeast extract to bacterium
2.5g/L, CaCO33g/L, pH 7.2) in.Condition of culture：30 degree, 220 rotating speeds cultivate 7 to 8 days time.
When culture was by the 7th or 8 day, zymotic fluid is collected, high speed centrifugation makes supernatant be detached with mycelium, and mycelium is added etc.
The acetone of amount breaks bacterium, and ultrasonic 20min rotates acetone, and supernatant is extracted using the ethyl acetate of equivalent with mycelium, is repeated once.
Concentrated by rotary evaporation obtains crude product HPLC detection products, three plants of bacterium is shown in view of HPLC results to dry, rear silicagel column crude separation
Yield comparison it is high.TLC contact plates have been carried out to the sample concentrated, and have been developed the color in iodine cylinder, it will be apparent that point snap out, use first
Alcohol dissolves, and high speed centrifugation takes supernatant to do the position that mass spectrum determines target point, has respectively obtained four kinds of compounds, and structural formula is respectively such as
Under：
Corresponding collection of illustrative plates is as shown in figures 1-4.
Below using with having structure J1001-2 sodium salts and J1-001 sodium salts as research object：
Research of the embodiment 2 using protein science and Phospoprotein group to J1001-2 sodium salts
(1) cell culture
MDA-MB-231 cells (three cloudy breast cancer cells) are with containing 10% fetal calf serum, 80 μ g/m L streptomysins, 80U/mL
The DEME of penicillin cultivates the CO based on 37 DEG C, 5%2Incubator routine culture.When cell covers with 90% or so, medicine is added
Object J1001-2 sodium salts.In protein groups experiment, 4 administration groups (administration concentration is 2 μM) are set, respectively for 24 hours, 48h, 72h with
And blank group (not dosing).In the experiment of phosphorylated protein group, be arranged 2 administration groups (administration concentration is 3 μM) be respectively 6h,
12h and blank group (not dosing).
(2) experimental method of protein science
1) protein groups sample preparation
Blank group and administration group cell are collected, is transferred in 1.5mL centrifuge tubes, 4 DEG C of centrifugation 5min of 2500rpm are abandoned
Clearly, cell precipitation be added 10 times of volumes cell pyrolysis liquid (8M urea, 100mM Tris, pH value 8) be resuspended and with it is ultrasonic with
Just albumen is extracted, rear 12000rpm is centrifuged in 15min, 4 DEG C of precooling 50% methanol/acetone, 50%/0.1% acetic acid of 3 times of volumes
It washes 3 times.(CaCl is resuspended in the buffer solution of 4M2, 8M urea, 0.2M Tris-HCl, pH value 8) and blow and beat uniformly after,
4 DEG C of centrifugations of 2500rpm, supernatant are transferred to a new EP pipe, and the DTT that 10mM is added is incubated 30min at 50 DEG C, uses
The IAA reagents of 40mM are alkylated 30min, and in 37 DEG C of overnight crack proteins of trypsin digestion, the desalination of SepPakC18 pillars is simultaneously true
Sky is dry.Peptide fragment from different component is mixed and passes through isolated 10 of strong cat ion exchange column with iTRAQ reagents label
Fraction enters MS analyses after by desalting column (C18 ZipTip) desalination.
2) protein group Mass Spectrometer Method and database retrieval
The instrument of Mass Spectrometer Method is TripleTOF 5600 (AB SCIEX).Peptide fragment after desalination is dissolved in containing 0.1%
Aqueous formic acid and acetonitrile (2%：98%) in, after be loaded into C18 trap columns (5 μm, 5x 0.3mm, Agilent
Technologies, Inc.) with 5 μ L/min flow velocitys, after passing through C18 analytical columns (75 μ m 150mm, 3 μm of particle
size,Pore size, Eksigent) with 300nL/min velocity separations 100min.Mobile phase is respectively：A phases are 3%
DMSO and 0.1% aqueous formic acid；The acetonitrile solution for the DMSO and 0.1% formic acid that B phases are 3%.With IDA mode detections MS/
MS, search sweep require to complete in 250ms, and scanning requires the ion for being collected into 20 products per 100ms.Ion range is set
It sets in 350-1500.The ion setting range of product is arranged in 100-1500.
Mass Spectrometer Method to initial data analyzed using ProteinPilot softwares, use Uniprot Homo sapiens
reference database(version:2015.8) database progress bioinformatic analysis.Arrange parameter is：Sample mould
Formula：iTRAQ4plex(Peptide Labeled)；Serine is alkylated：Iodoacetamide；Digestion：Trypsase；Search
Pattern：Quickly.
3) bioinformatic data analysis
The albumen adjusted uses KEGG pathway databases (http://www.genome.jp/kegg/) excavate assessment
Signal path (uses the automatic annotation service function KAAS of KEGG), and the albumen adjusted is uploaded for KAAS functional requirements.
4) data analysis
Come to the initial data of TripleTOF5600+ 5.0 softwares of ProteinPilot to analyze.Data search uses
The human protein group database of UniProt, arrange parameter has following：Sample type：Double methyl are quantitative ((0 ,+4 ,+8)；Silk
Propylhomoserin is alkylated：Iodoacetamide；Digestion：Trypsase；Specific factor：Emphasize phosphorylation.Way of search：Quickly.
(3) interpretation of result
As a result as shown in Figure 5 and Figure 6, wherein Fig. 5 is the cromoci changes of contents of J1001-2 inductions；Fig. 6 is indicated
The participation of J1001-2 inductions causes the raised albumen of calcium ion concentration.As can be seen that J1001-2 sodium salts act on cancer cell, energy
Enough modulin amount expression so that the albumen of regulating cell pigment C raises, such as UQCRC1 gene codes cytochromes
Cromoci (the Cytochrome b- of C (Cytochrome b-c1 complex subunit 1), UQCRC2 gene codes
C1 complex subunit 2), the cromocis (Cytochrome c1) of CYC1 gene codes, UQCRB gene codes
The cromoci of cromoci (Cytochrome b-c1 complex subunit 7), CYCS gene codes
(Cytochrome c), because cytochrome c (Cytochrome c) plays very important effect in apoptosis, this albumen position
Apoptosis inductions object can cause cytochrome c and is discharged into cytoplasm from mitochondria in gap between mitochondrial outer membrane and inner membrance,
And caspase-9 is activated with Apaf-1 combinations cytochrome cs/Apaf-1 compounds herein, and then activate caspase-3 under
The release of other caspases. cytochrome cs of trip is happened at activation and the DNA break of cysteine proteinase (caspases)
Before, it can be regarded as the beginning flag of apoptosis.Simultaneously so that regulation and control cause the raised GAP-associated protein GAP of calcium ion in tumour cell,
Because of intracellular Ca2+Excessively increasing can cause cell to overload, and calpain (Calpain) activity can be caused to increase, cause to dye
Body relaxation cause DNA expose and the release of calcium ion can be mitochondrial membrane permeability open release cromoci and
The apoptotic proteins enzyme activition factor (Apaf), the Apoptosis for being.Wherein participate in the albumen of calcium ion regulatory such as：ATP2B1 genes
The albumen (Plasma membrane calcium-transporting ATPase) of coding, the egg of SLC25A24 gene codes
The albumen of (Calcium-binding mitochondrial carrier protein), SLC25A13 gene codes in vain
The egg of (Calcium-binding mitochondrial carrier protein Aralar2), SLC25A12 gene codes
The egg of (Calcium-binding mitochondrial carrier protein Aralar1), ATP2A2 gene codes in vain
(Sarcoplasmic/endoplasmic reticulum calcium ATPase) in vain, the albumen of CAPNS1 gene codes
The albumen (Calpain-2catalytic subunit) of (Calpain small subunit 1), CAPN2 gene codes, from
And regulate and control a variety of metabolic pathways so that cancer cell multiplication differentiation is suppressed, and leads to apoptosis.
3 polyether compound of embodiment causes activity of tumor cells oxygen (ROS) to increase
1. experimental method
MDA-MB-231 cells (three cloudy breast cancer cells) are with containing 10% fetal calf serum, 80 μ g/m L streptomysins, 80U/mL
The DEME of penicillin cultivates the CO based on 37 DEG C, 5%2Incubator routine culture.When cell covers with 80% or so, medicine is added
Object J1001-1 or J1001-2.The mother liquid concentration of drug is 50mg/mL, the drug concentration being extremely arranged using PBS dilution drugs,
In administration group, 2 administration concentrations (1 μM and 4 μM), blank group (not dosing) are set.Drug treating time is 16 hours, repeats three
It is secondary.Using green skies active oxygen detection kit, is detected according to the experimental procedure that kit provides, Flow cytometry is used in combination to detect
The fluorescence intensity of blank group and administration group obtains the data of Fig. 7.
2. interpretation of result
From the point of view of experimental data, it has been found that J1001-1 and J1001-2 can cause ROS levels in tumour cell to increase
Add, for blank group, the ROS levels in the tumour cell of administration group significantly increase more than 10 times.J1001-1 and
Calcium ion concentration increases with concentration and is increased in tumour cell caused by J1001-2.
4 polyether compound of embodiment causes tumour cell calcium ion to increase
1. experimental method
MDA-MB-231 cells (three cloudy breast cancer cells) are with containing 10% fetal calf serum, 80 μ g/m L streptomysins, 80U/mL
The DEME of penicillin cultivates the CO based on 37 DEG C, 5%2Incubator routine culture.When cell covers with 80% or so, medicine is added
Object J1001-1 or J1001-2.The mother liquid concentration of drug is 50mg/mL, the drug concentration being extremely arranged using PBS dilution drugs,
In administration group, 2 administration concentrations (1 μM and 4 μM), blank group (not dosing) are set.Drug treating time is 16 hours, repeats three
It is secondary.Using green skies calcium ion detection kit, is detected according to the experimental procedure that kit provides, observe cell under the microscope
By fluorescing matter.It is used in combination the fluorescence intensity of Flow cytometry detection blank group and administration group to obtain the data of Fig. 8 and Fig. 9.
2. interpretation of result
From the point of view of experimental data, it has been found that J1001-1 and J1001-2 can cause calcium ion concentration in tumour cell
Increase, for blank group, the calcium ion concentration in the tumour cell of administration group significantly increases 2-3 times.J1001-1 exists
In tumour cell caused by 1 μM calcium ion concentration and J1001-1 in the tumour cell caused by 4 μM calcium ion concentration it is suitable；
Calcium ion concentration increases with concentration and is increased in tumour cell caused by J1001-2.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office
It can be combined in any suitable manner in one or more embodiments or example.In addition, without conflicting with each other, the skill of this field
Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples
It closes and combines.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changes, replacing and modification.
Claims (9)
1. the purposes of polyether compound in medicine preparation, which is characterized in that the drug is at least one following for regulating and controlling
Signal path：By influence calcium ion induction apoptosis, by influence the horizontal apoptosis mediated of reactive oxygen species (ROS),
The apoptosis that the cromoci level of cell mitochondrial mediates is influenced,
The polyether compound has one of following structure：
2. purposes according to claim 1, which is characterized in that the drug regulates and controls institute by least one following form
State apoptotic signal access：
Ca ion concentrations are activated to rise；
Activate the up-regulation of ROS levels；
Active cell pigment C horizontal expressions.
3. purposes according to claim 1, which is characterized in that the drug is by promoting Ca ion concentrations to rise, regulation and control
The apoptotic signal access.
4. purposes according to claim 1, which is characterized in that the drug activates ROS levels to raise by promotion, regulation and control
The apoptotic signal access.
5. purposes according to claim 1, which is characterized in that the drug is adjusted by promoting cromoci horizontal expression
Control the apoptotic signal access.
6. purposes according to claim 1, which is characterized in that the drug is regulated and controled thin by least one following form
The level of Cytochrome C：
Promote cromoci (the Cytochrome b-c1complex subunit 1) expression of UQCRC1 gene codes；
Promote cromoci (the Cytochrome b-c1complex subunit 2) expression of UQCRC2 gene codes；
Promote cromoci (Cytochrome c1) expression of CYC1 gene codes；
Promote cromoci (the Cytochrome b-c1complex subunit 7) expression of UQCRB gene codes；
Promote the cromoci (Cytochrome c) of CYCS gene codes.
7. purposes according to claim 1, which is characterized in that the drug is regulated and controled swollen by least one following form
The level of calcium ion in oncocyte：
Promote albumen (Plasma membrane calcium-transporting ATPase) table of ATP2B1 gene codes
It reaches；
Promote the albumen (Calcium-binding mitochondrial carrier protein) of SLC25A24 gene codes
Expression；
Promote albumen (the Calcium-binding mitochondrial carrier protein of SLC25A13 gene codes
Aralar2 it) expresses；
Promote albumen (the Calcium-binding mitochondrial carrier protein of SLC25A12 gene codes
Aralar1 it) expresses；
Promote albumen (the Sarcoplasmic/endoplasmic reticulum calcium of ATP2A2 gene codes
ATPase it) expresses；
Promote albumen (the Calpain small subunit 1) expression of CAPNS1 gene codes；
Promote albumen (the Calpain-2 catalytic subunit) expression of CAPN2 gene codes；
The concentration of the calcium ion in tumour cell is promoted to increase.
8. a method of screening anticancer drug, which is characterized in that including：
(1) Candidate Agents are contacted with cancer cell, and detect whether the front and back signal path of contact is adjusted,
The signal path includes at least one of following：
By influencing the apoptosis of calcium ion induction, by influencing the horizontal apoptosis mediated of reactive oxygen species (ROS), influencing cell
The apoptosis that the cromoci level of mitochondria mediates；
(2) after the contact, the signal path is adjusted the instruction for being the Candidate Agents as the anticancer drug.
9. according to the method described in claim 7, in step (1), the expression of at least one following albumen before and after contacting is detected
Amount：Calcium ion concentration, active oxygen (ROS) level, cromoci etc.；
It is after contact, described in step (2)：At least one calcium ion concentration, active oxygen (ROS) level, cromoci
Expression quantity increase is instruction of the Candidate Agents as the anticancer drug.
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